| M.Willem, Tahirovic, Busche, Ovsepian, Chafai, Kootar, Hornburg, Evans, Moore, Daria, Hampel, Mueller, Giudici, Nuscher, Kremmer, Heneka, Thal, Lannfelt, Mueller, Livesey, Meissner, Herms, Konnerth, M
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 Alzheimer disease (AD) is characterized by the accumulation of
amyloid plaques, which are predominantly composed of amyloid-b
peptide1. Two principal physiological pathways either prevent or
promote amyloid-b generation from its precursor, b-amyloid precursor
protein (APP), in a competitive manner1. Although APP
processing has been studied in great detail, unknown proteolytic
events seem to hinder stoichiometric analyses of APP metabolism
in vivo2. Here we describe a new physiological APP processing
pathway, which generates proteolytic fragments capable of inhibiting
neuronal activity within the hippocampus.Weidentify higher
molecular mass carboxy-terminal fragments (CTFs) of APP,
termed CTF-g, in addition to the long-known CTF-a and CTF-b
fragments generated by the a- and b-secretases ADAM10 (a disintegrin
and metalloproteinase 10) and BACE1 (b-site APP cleaving
enzyme 1), respectively. CTF-g generation is mediated in part by
membrane-bound matrix metalloproteinases such as MT5-MMP,
referred to as g-secretase activity. g-Secretase cleavage occurs
primarily at amino acids 504–505 of APP695, releasing a truncated
ectodomain. After shedding of this ectodomain, CTF-g is further
processed by ADAM10 and BACE1 to release long and short Ag
peptides (termed Ag-a and Ag-b). CTFs produced by g-secretase
are enriched in dystrophic neurites in an AD mouse model and in
human AD brains. Genetic and pharmacological inhibition of
BACE1 activity results in robust accumulation of CTF-g and
Ag-a. In mice treated with a potent BACE1 inhibitor, hippocampal
long-term potentiation was reduced. Notably, when recombinant
or synthetic Ag-a was applied on hippocampal slices ex vivo, longterm
potentiation was lowered. Furthermore, in vivo single-cell
two-photon calcium imaging showed that hippocampal neuronal
activity was attenuated by Ag-a. These findings not only demonstrate
a major functionally relevant APP processing pathway,
but may also indicate potential translational relevance for therapeutic
strategies targeting APP processing.
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